Molecule Involved in Fasting Adaptations Could Unlock Anti-Obesity Strategies

When fasting or facing a food shortage, the body engages metabolic and behavioral adaptations to survive. How the brain coordinates and regulates these responses has not been clear, but researchers at Baylor College of Medicine, and collaborating institutions, have now discovered that a molecule known as steroid receptor coactivator-2 (SRC-2) is crucial to coordinate the biological responses to the lack of food.

The team’s studies found that SRC-2 specifically in pro-opiomelanocortin (POMC) neurons in the hypothalamus—a brain region involved in various aspects of metabolism, including energy management—helps animals modify their metabolism and certain behaviors to survive until food is available again. Interestingly, SRC-2 was also found to be involved in weight gain when food was abundant, leading to obesity. The findings open new possibilities for designing strategies for weight management.

“When food is not easily available or during fasting, organisms modify certain aspects of their metabolism to be able to function and of their behavior to improve the odds of restoring the much-needed nutrition,” said Yong Xu, MD, PhD, professor of pediatrics, nutrition and molecular and cellular biology at Baylor. “In this study, we show that SCR-2 in POMC neurons in the hypothalamus is at the center of these adaptations.”

Xu is corresponding author of the team’s published paper in Cell Reports, which is titled, “Hypothalamic steroid receptor coactivator-2 regulates adaptations to fasting and overnutrition,” and in which the authors concluded, “Collectively, our results identified hypothalamic SRC-2 as a key molecule that coordinates multifaceted adaptive responses to food shortage and promotes body weight gain in the context of overnutrition.”

During the course of evolution, animals (including humans) are challenged by periods of food shortage, the authors noted. When animals are subjected to food deprivation, the neuroendocrine system coordinates “enormous metabolic and behavioral adaptations” to help ensure the animal’s survival. “These include suppression of energy expenditure to preserve energy, prevention of severe hypoglycemia to keep the brain nourished and alert, reducing anxiety and fear to facilitate searching for food that may be associated with danger, and suppression of satiation to ensure efficient refeeding when food becomes available again,” the team noted.

The hypothalamus plays a key role in maintaining energy homeostasis, by integrating information regarding the nutritional status of the body, and then orchestrating endocrine and behavioral responses. “In particular, pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARH) have been identified as the first-order neurons that respond to multiple hormonal and nutritional signals to regulate energy and glucose metabolism,” the researchers noted. “However, the roles of POMC neurons in coping with food deprivation are not fully understood.” For their research, the Baylor researchers and colleagues looked at the activity of steroid receptor coactivator-2 (SRC-2), which is one of a family of nuclear receptor coactivators that regulate how nuclear receptors and transcription factors can modulate target gene expression. In particular, Xu and colleagues looked into two important metabolic components: energy expenditure and blood glucose balance.

Their studies, including work in POMC-specific SRC-2 knockout (KO) mice, found that loss of SRC-2 in POMC neurons impaired the animals’ ability to suppress energy expenditure during food deprivation, leading to greater loss of body weight. “Importantly, the mutant mice lost more body weight and fat storage after food deprivation, indicating that the small deficits in suppressing energy expenditure in these mice are sufficient to result in significant damage to energy balance,” the team stated.

The studies also indicated that SRC-2 in POMC neurons was essential for mechanisms to prevent severe hypoglycemia. “One way to adapt to lack of food is to reduce how much energy the body spends, Xu said. “It is also important that the body maintains a glucose balance that sustains brain activity. We found that SRC-2 is required to retain the ability to reduce energy expenditure and to maintain glucose levels that allow the animal to survive.” As the authors pointed out, “The loss of SRC-2 in POMC neurons also impairs counterregulatory responses and causes glucose dysregulations, especially during the hypoglycemic challenge.” These deficits combined, the team suggested, “would render major disadvantages to animals’ survival if they lived in a real wild environment with frequent periods of fasting.”

The researchers also looked into behavioral adaptations that help the animal find food. “When an animal living in the wild has not eaten in a while, it needs to venture into its environment to search for food, which at the same time exposes it to predators, creating anxiety,” Xu said. “We found that SRC-2 helps overcome the anxiety triggered by the need to go out to feed, facilitating the search for food.” As they reported in their paper, “These results indicate that SRC-2 in POMC neurons does not regulate anxiety per se but rather facilitates animal’s mood adaptations to seek for food that is associated with potential danger.”

In addition, the scientists found that SRC-2 is required to delay the normal satiety signal that stops the animal from eating. “Delaying the satiety signal stimulates the animal to engage in continuous feeding behavior longer, eating as much as possible, quickly, to reduce the time they are exposed to a dangerous environment.” But for the experimental mice that lack SRC-2 in POMC neurons, “when food becomes available, these mutant mice show insufficient refeeding associated with enhanced satiation and discoordination of anxiety and food-seeking behavior.”

During most of evolution, having enough food has been, and still is, the first priority of animals in the wild. Xu and colleagues propose that SRC-2 is evolutionarily conserved, meaning that it is at the center of the regulation of animal metabolic and behavioral adaptations that help organisms survive when food is not easily available.

On the other hand, when the environment changes so that food is readily available, animals can eat without limitations. “In this case, SRC-2 becomes detrimental to the animals. It facilitates overeating, leading to weight gain and obesity,” Xu said.

At the mechanistic level, Xu and colleagues showed that SRC-2 controls the ability of POMC neurons to transmit electrical signals to communicate with other neurons. SRC-2 also mediates its effects by regulating the expression of multiple genes. “SRC-2 coactivates Forkhead box protein O1 (FoxO1) to suppress POMC gene expression,” they wrote. “Notably, loss of FoxO1 in POMC neurons results in similar impairment in fasting-induced refeeding, as we observed in mice lacking SRC-2 in POMC neurons, further highlighting an important role of SRC-2/FoxO1 signaling in physiological responses during the fasting-refeeding transition.”